or two amino acids in the molecular structure. There would appear to be differences
in the structure of the receptors, as well as the hormones, in different species, the
magnitude of the response being related to how favourable an interaction between
the two is possible. Apart from their concentration this depends on the steric configurations and electrical charges of the hormones and receptors. Once the molecules are suitably aligned and in apposition it is possible that some chemical interaction occurs, which could involve the disulphide bridge of the hormone and
sulphydryl groups on the receptor. This suggestion has not gained consensus
however; since the hormone onl y acts when present at the serosal side, th e receptors
may be present at this surface.
Subsequent to th e primary interaction of the hormone and receptor, the enzyme
adenyl cyclase is activated and cyclic AMP is formed from ATP. This observation
was originally made by ORLOFF and HANDLER (1962,1967), using the isolated toad
urinary bladder, and constitutes a major advance in our ideas about the hormone's
action. C yclic AMP subsequently initiates an increased permeability of the membrane to water and sodium, but the details of how this is brought about are unknown. The nucleotide activates phosphorylase and is destroyed by another enzyme, phosphodiesterase. The process of the hormones action can be blocked at
various points; neurohypophysial peptides with little biological activity can reduce
the activity of vasotocin by excluding it from its receptor site (MOREL and lARD,
1963), Ca
H
and Mn
H
block the hormone's effect but not that of cyclic AMP, while
Zn
H
also blo cks the nucleotide (BENTLEY , 1967). Xanthines, like theophylline and
caffeine , inhibit phosphodiesterase and so imitate the action of the hormone by
preventing the breakdown of endogenous cyclic AMP (ORLOFF and HANDLER ,
1962). Though the dual increased permeability to water and to sodium can be demonstrated in the toad bladder (and skin), these effects are physiologically separate,
and it seems likely that the nucleotides that mediate each effect are separated. This
could be an anatomical sequestration, such as that involving 'granulated' and 'mitocho ndria-rich' cells.
Water moves more readily down an osmotic gradient across the bladder in the
presence of neurohypophysial hormones. This normally takes place from the mucosal to serosal side, but if the gradient is reversed in vitro, acceleration can also
be shown to occur from the serosal to mucosal surface. Thus it is clear that no special energy input mechanism, to account directly for the water movement, need
be postulated. The effect is indeed relativel y independent of metabolism, and still
can be shown to occur after the tissue has been exposed to cyanide or dinitrophenol.
The site of the effector change in the epithelial cells is generally thought to he the
cell membrane on the mucosal side of the bladder, though the evidence for th is
is equivocal. Changes in permeability to water can be measured in two ways; in
the presence of an osmotic gradient (osmotic permeability), or in its absence, with
the aid of the labelled water molecules, deuterium or tr itium (diffusion permeability) . Neurohypophysial peptides have a greater effect on the osmotic than
diffusion permeability and this has been interpreted to indicate that the hormones
increase 'bulk' flow of water through pores. This suggestion would be consistent
with an increase in the diameter of such pores (rather than the total pore surface
area, which is directly related to movement by diffusion). The evidence is circumstantial, but affords an explanation of the observations. Such changes in pore size
84
in the structure of the receptors, as well as the hormones, in different species, the
magnitude of the response being related to how favourable an interaction between
the two is possible. Apart from their concentration this depends on the steric configurations and electrical charges of the hormones and receptors. Once the molecules are suitably aligned and in apposition it is possible that some chemical interaction occurs, which could involve the disulphide bridge of the hormone and
sulphydryl groups on the receptor. This suggestion has not gained consensus
however; since the hormone onl y acts when present at the serosal side, th e receptors
may be present at this surface.
Subsequent to th e primary interaction of the hormone and receptor, the enzyme
adenyl cyclase is activated and cyclic AMP is formed from ATP. This observation
was originally made by ORLOFF and HANDLER (1962,1967), using the isolated toad
urinary bladder, and constitutes a major advance in our ideas about the hormone's
action. C yclic AMP subsequently initiates an increased permeability of the membrane to water and sodium, but the details of how this is brought about are unknown. The nucleotide activates phosphorylase and is destroyed by another enzyme, phosphodiesterase. The process of the hormones action can be blocked at
various points; neurohypophysial peptides with little biological activity can reduce
the activity of vasotocin by excluding it from its receptor site (MOREL and lARD,
1963), Ca
H
and Mn
H
block the hormone's effect but not that of cyclic AMP, while
Zn
H
also blo cks the nucleotide (BENTLEY , 1967). Xanthines, like theophylline and
caffeine , inhibit phosphodiesterase and so imitate the action of the hormone by
preventing the breakdown of endogenous cyclic AMP (ORLOFF and HANDLER ,
1962). Though the dual increased permeability to water and to sodium can be demonstrated in the toad bladder (and skin), these effects are physiologically separate,
and it seems likely that the nucleotides that mediate each effect are separated. This
could be an anatomical sequestration, such as that involving 'granulated' and 'mitocho ndria-rich' cells.
Water moves more readily down an osmotic gradient across the bladder in the
presence of neurohypophysial hormones. This normally takes place from the mucosal to serosal side, but if the gradient is reversed in vitro, acceleration can also
be shown to occur from the serosal to mucosal surface. Thus it is clear that no special energy input mechanism, to account directly for the water movement, need
be postulated. The effect is indeed relativel y independent of metabolism, and still
can be shown to occur after the tissue has been exposed to cyanide or dinitrophenol.
The site of the effector change in the epithelial cells is generally thought to he the
cell membrane on the mucosal side of the bladder, though the evidence for th is
is equivocal. Changes in permeability to water can be measured in two ways; in
the presence of an osmotic gradient (osmotic permeability), or in its absence, with
the aid of the labelled water molecules, deuterium or tr itium (diffusion permeability) . Neurohypophysial peptides have a greater effect on the osmotic than
diffusion permeability and this has been interpreted to indicate that the hormones
increase 'bulk' flow of water through pores. This suggestion would be consistent
with an increase in the diameter of such pores (rather than the total pore surface
area, which is directly related to movement by diffusion). The evidence is circumstantial, but affords an explanation of the observations. Such changes in pore size
84